4-heteroaryl- and 4-aryl-1,4-dihydropyridine compounds

Abstract

There are provided novel 1,4-dihydropyridine compounds, compositions containing them and methods of using them to treat congestive heart failure.

Description

This is division of application Ser. No. 07/549,821, filed Jul. 9, 1990, now U.S. Pat. No. 5,166,147.

FIELD OF THE INVENTION

This invention relates to certain novel 1,4-dihydropyridines, processes for their preparation, pharmaceutical compositions containing them, and methods of using them to treat congestive heart failure, and more particularly to such 1,4-dihydropyridines having both calcium agonist and alpha₁ -antagonist activity and which are useful in the treatment of congestive heart failure.

BACKGROUND OF THE INVENTION

Over the past decade, dihydropyridine calcium antagonists or calcium channel blockers have become widely known therapeutic agents having vasodilator properties which can be used as antihypertensives and coronary dilator agents. These compounds inhibit the entry of calcium ions into cells, or its mobilization from intracellular stores. More recently, it has been found that small structural modifications of these known compounds produce dihydropyridines with effects diametrically opposed to those of calcium channel blockers. Dihydropyridines such as Bay K8644 and CGP 28392 (FIG. 1) promote an influx of calcium ions, into cells thereby producing positive inotropic and vasoconstrictor effects. Bay K8644 is more than ten times as potent as CGP 28392 as a calcium agonist. However, Bay K8644 is not useful as a cardiotonic because of its coronary vasoconstricting properties. Therefore it is only useful as a pharmacological tool to ascertain the function of calcium entry blockers. ##STR1##

Representative of the art in the field of dihydropyridine calcium agonists are U.S. Pat. No. 4,248,873 (Bosserr et al.) issued Feb. 3, 1981, European Patent Application 0071819 published Feb. 16, 1983 (Boshagen et al.), U.S. Pat. No. 4,537,881 (Franckowiah et al.) issued Aug. 27, 1985 and U.S. Pat. No. 4,532,248 issued Jul. 30, 1985 which describes dihydropyridine calcium agonists which contain an amino group in the 2-position. Literature references include M. Schram, et al., Nature, 303, 535 (1983); M. Schram, et al., Arzneim-Forsch., 33, 1268 (1983); P. Erne, et al., Biochem. Biophys. Res. Commun., 118, 842 (1984).

Combining calcium agonist properties and alpha₁ -adrenergic blocking properties in a single molecular structure provides a new and attractive principle for the treatment of congestive heart failure. The combination of these two types of activities affords a novel class of cardiotonics which have cardiac stimulatory effects in combination with pronounced vasodilator properties. The detrimental vasoconstricting properties which are normally associated with dihydropyridine calcium agonists are minimized by the alpha₁ -adrenergic blocking properties which cause dilation of the peripheral vasculature. Applicants are not aware of any references that describe the combination of these actions in a single compound, other than co-assigned U.S. Pat. 4,868,181 (Johnson et al.) issued Sep. 19, 1989.

SUMMARY OF THE INVENTION

According to the present invention there is provided novel 1,4-dihydropyridine derivatives of the general formula (I) which possess both calcium channel promoting activity and alpha₁ -adrenergic blocking properties and are useful in the treatment of congestive heart failure. These compounds have the formula: ##STR2## or a pharmaceutically acceptable salt thereof or an optically active isomer or N-oxide thereof wherein:

R² and R⁶ independently are alkyl of 1-4 carbon atoms, CN, CH₂ OH or CH₂ OCH₂ CH₂ NH₂ ;

R³ independently is NO₂, H, CN, CONH₂, or taken together with R² is ##STR3## Cy, when R⁵ is CHO, COCH₃, CO₂ CH₂ CHOHC₆ H₅, CO₂ CH(OCH₃)C₆ H₅, NO₂, CONHC₆ H₅ or an alkyl ester of 1-10 carbon atoms, is: ##STR4## R¹ and R⁹ independently are H, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen or NO₂ ;

Cy, when R⁵ is COR⁷, CO₂ R⁷ or CONHR⁷, is: 3-, or 4-pyridinyl; 2- or 3-furanyl; 2- or 3-thienyl, 4-, or 5-thiazolyl, 2-, 4-, or 5-pyrimidinyl or ##STR5## X is SO, SO₂, NR⁴, O, S or N→O; ##STR6## R⁴ is H or an alkyl group of 1-4 carbon atoms; ##STR7## A is a straight or branched alkyl, alkenyl, or alkynyl chain or --(CH₂)_n CHOHCH₂ --; ##STR8## or 2-, 3-, or 4-pyridinyl; 2-, or 4-pyrimidinyl; or 2-pyrazinyl; ##STR9## Ar is phenyl optionally substituted with one or two substituents independently selected from the group consisting of:

alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, or NO₂, provided that Ar is not 4-fluorophenyl;

Q is (CH₂)_q, (CH₂)_n O, (CH₂)_n NH or (CH₂)_n S;

n is independently 1-4;

p is 1 to 10;

q is 0-2; and

r is 1 to 10, with the following proviso: ##STR10## when Cy is and X is O, S or NH, then

R⁷ cannot be --(A)_r --NH--Q--Ar, where A is as defined above;

R⁸ cannot be Ar; and

R¹0 cannot be 2-, 3-, or 4-pyridinyl or 2-, or 4-pyrimidinyl.

The compounds of the present invention can exist as optical isomers and both the racemates as well as the individual optical isomer which confers agonist activity are within the scope of the present invention. The racemic mixtures can be separated into their individual isomers by well known techniques such as the separation of the diastereomeric salts formed with optically active acids, followed by conversion back to the optically active 1,4-dihydropyridine.

Also provided are pharmaceutical compositions comprising a suitable pharmaceutical carrier and a compound of formula (I) and methods of using the compounds of formula (I) to treat congestive heart failure.

Further provided are processes for preparing compounds of formula (I), which processes will be described in detail hereinafter.

PREFERRED EMBODIMENTS

Preferred compounds are those of formula (I) wherein:

(A)

(1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR11## (3) Cy is and/or

(4) R⁵ is an alkyl ester of 1-4 carbon atoms, wherein:

(a) R¹ is H; and/or

(b) Y is CH₂ and/or

(c) R⁷ is ##STR12## wherein (i) A is --(CH₂)_p -- where p is 1 to 5; and/or

(ii) R⁸ is Ar where Ar is phenyl optionally monosubstituted with OCH₃, CH₃, or Cl; or R⁸ is ##STR13## (iii) R¹0 is 2- or 4-pyrimidinyl. (B)

(1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR14## (3) Cy is and/or

(4) R⁵ is an alkyl ester of 1-4 carbon atoms, wherein;

(a) R¹ is H; and/or

(b) X is O; and/or

(c) R⁷ is ##STR15## wherein: (i) A is --(CH₂)_p --(P=1-5); and/or

(ii) R⁸ is selected from the group consisting of: ##STR16## (C) (1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR17## (3) Cy is and/or

(4) R⁵ is an alkyl ester of 1-4 carbon atoms, wherein;

(a) R¹ is H; and/or

(b) X is SO₂ ; and/or

(c) R⁷ is ##STR18## wherein: (i) A is --(CH₂)_p --(P=1-5); and/or

(ii) R⁸ is Ar, where Ar is phenyl optionally monosubstituted with OCH₃, CH₃ or Cl, or is selected from the group consisting of: ##STR19## (D) (1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or

(3) Cy is 2- or 3-furanyl; 2- or 3-thienyl; 3-pyridinyl; ##STR20## and/or (4) R⁵ is CO₂ R⁷ ; where;

(a) R⁷ is ##STR21## wherein: (i) A is --(CH₂)_p --(p=1-5); and/or

(ii) R⁸ is Ar where Ar is phenyl optionally monosubstituted with OCH₃, CH₃, or Cl; and/or

(iii) R¹0 is 2- or 4-pyrimidinyl.

Specifically Preferred Compounds

(1) 1,4-Dihydro-4-(2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-furanyl)- 2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, methyl ester

(2) 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, {4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl} ester

(3) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylic acid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(4) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(5) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, {2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl} ester

(6) 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, {4-[4-(2-methoxyphenyl)1-piperazinyl]butyl} ester

(7) 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(8) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-thienyl)-3-pyridinecarboxylic acid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(9) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-thienyl)-3-pyridinecarboxylic acid, {2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl} ester

(10) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(11) 4-(2-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(12) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(2-thienyl)-3-pyridinecarboxylic acid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(13) 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(14) 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, {2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl} ester

Detailed Description of the Invention

Synthesis

The dihydropyridines of the general formula (I), can be prepared by the processes illustrated below. It is understood in all of these processes that R¹ -R¹0, Ar, X, Y, A, p, r, Q, n, q are as defined above. Methods A-F are substantially the same as described in commonly assigned U.S. Pat. No. 4,868,181 which is herein incorporated by reference.

Compounds of the formula CyCHO (2) are commercially available, or may be prepared by methods described in the literature. The heterocyclic aldehydes used as intermediates are available by methods described in standard works on heterocyclic chemistry such as Katritzsky and Rees, Comprehensive Heterocyclic Chemistry, vols. 2-5, Pergamon Press, N.Y., 1984. In some instances, the preparation of the hydroxymethyl compounds are described in the literature. These can be converted to the corresponding aldehydes by known methods, such as oxidation with manganese dioxide, or dimethysulfoxide activated with oxalyl chloride.

Compounds of the formula 6 may be prepared according to Method 1, where X" is NR⁴, O, or S, and R¹2 is CO₂ R⁴ or CH₂ OH (or a protected alcohol). Compound 3 is alkylated with an appropriate connector chain 4 to give compound 5. This reaction is carried out in the presence of an aromatic hydrocarbon such as benzene, toluene, etc., a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride, etc., an ether such as THF, DME, etc., or an aprotic solvent such as acetonitrile, DMF, etc., in the presence of a base such as potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium hydride, at a temperature in the range of -20°C to 200°C preferably of 25°C to 150°C Separation of the desired product from the reaction mixture is effected by conventional operations such as filtration, concentration, extraction, column chromatography, recrystallization, etc. ##STR22##

Compounds of the formulas 7, 8, 9, and 10 may be purchased commercially, or prepared according to the methods described by S. F. Campbell, et al., J. Med. Chem., 30, 49, 999, 1794 (1987), and by other methods reported in the literature. ##STR23##

Compounds of the formula 13 may be prepared according to Method 2. Compound 11 (prepared according to Methods A-D) is converted to the carboxylic acid with a fluoride source, such as tetrabutylammonium fluoride or hydrogen fluoride. Treatment with 1,1'-carbonyldiimidazole provides the activated imidazolide 12, which may be reacted with alcohols of the type R⁷ OH to produce 13. ##STR24##

As shown in Method 3, compounds of the formulas 15 and 17 may be prepared by reacting compounds of the formulas 14 and 16 with amines 7 or 8 or 9 or 10, respectively. The reaction is carried out by reacting 14 or 16 with amines 7 or 8 or 9 or 10 in a molar ratio of 1.0:1.0 to 1.0:4.0 in the presence of a base such as potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, or sodium hydroxide. The reaction is performed in the presence of an alcoholic solvent such as methanol, ethanol, i-propanol or n-butanol, an aromatic hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran (THF) or dioxane, a halogenated hydrocarbon such as chloroform or carbon tetrachloride, an aprotic polar solvent such as acetonitrile, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or the like at a temperature in the range of room temperature to 200°C, preferably at about 25°C-110°C Separation of the desired product from the reaction mixture is effected by conventional techniques such as filtration, concentration, extraction, column chromatography, recrystallization, etc.

This method is also applicable for compounds of the Formula 16, where Y or Z is substituted for X. ##STR25##

Where X is NR⁴ or S, 17 can be oxidized to R⁴ N→O or SO or SO₂, respectively, with an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, etc.

Compounds of the formula 19, where R¹3 is S or O, (Method 4) may be prepared according to procedures described in the literature, such as I. Sircar, et al., Tetrahedron Lett. 29, 6835 (1988) and U.S. Pat. No. 4,642,310, issued Feb. 10, 1987. ##STR26##

The above preparation processes are given merely for illustration. The preparation of the compounds of the formula (I) is not limited to these processes, but any modification of these processes can be applied in the same manner to the preparation of the compounds according to the invention.

A resulting basic compound can be converted into a corresponding acid addition salt by reacting it with an inorganic or organic acid as is well known to one skilled in the art. Therapeutically useful acids include, for example, inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric or nitric, or organic acids, such as formic, acetic, propionic, succinic, maleic, fumaric, tartaric or ascorbic acid.

The compounds of this invention and their preparation can be understood further by the following examples, but should not constitute a limitation thereof. In these examples, unless otherwise indicated, all temperatures are in degrees Celsius and parts and percentages are by weight.

EXAMPLE 1

Part A; 2-(5-Chloropentyl)-3-furanmethanol: To a solution of 3-furanmethanol (3.56 g) in THF (200 ml) at -20°C, was added n-butyllithium (50 ml of 1.6M in hexane). The solution was kept at 0°C for 4 hrs., then 5-chloro-1-iodopentane (8.37 g) was added. The mixture was stirred at room temperature for 4 days, after which water (500 ml) and ether (500 ml) were added. The organic layer was separated and dried over magnesium sulfate and the solvent was removed by rotary evaporation to give an oil. Purification by column chromatography on silica gel, using hexane:ethyl acetate (1:1) as the eluent provided the pure product, 5.6 g. ¹ H-NMR (CDCl₃) ∂1.50 (m, 2H); 1.67 (m, 2H); 1.80 (m, 2H); 2.64 (t, 2H, J=7 Hz); 3.52 (t, 2H, J=7 Hz); 4.46 (s, 2H); 6.04 (s, 1H); 6.36 (s, 1H).

Part B; 2-(5-Chloropentyl)-3-furanaldehyde: To a 500 ml 4-neck round-bottom flask fitted with mechanical stirrer, thermowell, and addition funnel, under a nitrogen atmosphere, was added 7.4 ml of oxalyl chloride and 150 ml of dichloromethane. The reaction was cooled to -78°C with a dry ice/acetone bath. Then 12.58 ml of distilled dimethylsulfoxide in 38 ml of dichloromethane was added dropwise, maintaining the reaction temperature below -65°C After the addition was complete, 15 g of 2-(5-chloropentyl)-3-furanmethanol was added in 74 ml of dichloromethane. After addition was complete, the mixture was stirred for 30 min., then 52 ml of triethylamine was added. The bath was allowed to warm gradually to room temperature, and stirred overnight at this temperature. The reaction mixture was poured into a 1 liter flask containing a stirring mixture of 310 g of crushed ice and 47 ml of 1N HCl. After stirring for 30 min., the mixture was extracted with dichloromethane (3×100 ml). The organic solution was dried over magnesium sulfate, filtered and concentrated to a brown oil. The product was further purified by column chromatography on silica gel, eluting with 10% ethyl acetate in hexane to give 12.75 g of the purified product as an oil. ¹ H-NMR (CDCl₃) ∂1.52 (m, 2H); 1.79 (m, 4H); 2.98 (t, 2H, J=7 Hz); 3.54 (t, 2H, J=7 Hz); 6.70 (d, 1H, J=2 Hz); 7.33 (d, 1H, J=2 Hz); 9.95 (s, 1H).

Part C; 1,4-Dihydro-4-[2-(5-chloropentyl)-3-furanyl]-2,6-dimethyl-5-nitro-3-pyridi necarboxylic acid, methyl ester: A mixture of 2-(5-chloropentyl)-3-furanaldehyde (10.2 g), nitroacetone (7.9 g), and methyl 3-aminocrotonate (5.9 g) in 250 ml of ethanol was heated at reflux for 18 hrs. After removal of the solvent by rotary evaporation, the residue was purified via column chromatography on silica gel, eluting with 30% petroleum ether in diethyl ether, to give a yellow solid. Recrystallization from chloroform/diethyl ether produced yellow crystals, 3.2 g, m.p. 133°-135°C ¹ H-NMR (CDCl₃) ∂1.65 (m, 4H); 1.87 (m, 2H); 2.36 (s, 3H); 2.52 (s, 3H); 2.78 (m, 2H); 3.56 (t, 2H, J=7 Hz); 3.69 (s, 3H); 5.29 (s, 1H); 5.98 (s, 1H); 6.07 (d, 1H, J=1 Hz); 7.14 (d, 1H, J=1 Hz). Mass spectrum: 383 (M+H). IR (KBr): 3311, 2952, 1706, 1654, 1491, 1450, 1220 cm-1.

Part D; 1,4-Dihydro-4-(2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-furanyl)- 2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, methyl ester: A mixture of 1,4-dihydro-4-[2-(5-chloropentyl)-3-furanyl]-2,6-dimethyl-5-nitro-3-pyridi necarboxylic acid, methyl ester (1.0 g), 0.9 g of 1-(2-methoxyphenyl)piperazine, 75 mg of sodium iodide, and 0.4 g of sodium bicarbonate in 100 ml of acetonitrile was heated at reflux for 6.5 hrs., then stirred overnight at room temperature. The solvent was removed by rotary evaporation, and the residue was part it ioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (2×100 ml), the organic layers combined, washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, eluting with 5% methanol in dichloromethane. The product (Ex. No. 1, Table 1) was isolated as an orange solid, 1.07 g., m.p. 94°-105°C ¹ H-NMR (CDCl₃) ∂1.45 (m, 2H); 1.69 (m, 6H); 2.37 (s, 3H): 2.51 (m, 1H); 2.77 (m, 5H); 3.28 (m, 4H); 3.68 (s, 3H); 3.87 (s, 3H); 5.30 (s, 1H); 6.11 (d, 1H, J=2 Hz); 6.30 (br. s., 1H); 6.95 (m, 4H); 7.14 (d, 1H, J=2 Hz). IR (KBr): 2942, 1709, 1651, 1501, 1317, 1225 cm-1. Mass Spectrum: 539 (M+1), 211 (DHP nucleus). HRMS: Calcd: 538.2791; Found: 538.2795

EXAMPLE 53

Part A; 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylic acid, (4-chlorobutyl) ester: A mixture of nitroacetone (3.41 g), 3-pyridinecarboxaldehyde (2.36 g), and (4-chlorobutyl)-3-aminocrotonate (4.22 g) in 100 ml ethanol was heated to reflux for 4 hrs., then stirred at room temperature for 16 hrs. After removal of the solvent by rotary evaporation, the residue was purified via column chromatography on silica gel, eluting with 15% methanol in ethyl acetate, to give a yellow solid, 4.13 g, m.p. 153°-156°C (dec). ¹ H-NMR (CDCl₃) ∂1.72 (m, 4H); 2.37 (s, 3H); 2.52 (s, 3H); 3.50 (t, 2H, J=6 Hz); 4.10 (t, 2H, J=6 Hz); 5.38 (s, 1H); 7.26 (dd, 1H, J=8, 5 Hz); 7.77 (dd, 1H, J=2, 8 Hz); 8.01 (s, 1H); 8.43 (dd, 1H, J=2, 5 Hz); 8.50 (d, 1H, J=2 Hz). Mass spectrum: 366 (M+H).

Part B; 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylic acid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester: To a 100 ml 3-neck round-bottom flask fitted with mechanical stirrer, reflux condenser, and thermowell, under a nitrogen atmosphere, was added 1.0 g of 1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylic acid, (4-chlorobutyl) ester, 80 ml of DME, 1.79 g of 1-(2-pyrimidinyl)piperazine, 0.10 g of sodium iodide, and 0.5 g of sodium bicarbonate. The reaction mixture was heated at reflux overnight. The solvent was removed by rotary evaporation, and the residue was partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (2×200 ml), the organic layers combined, washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, eluting with 10% methanol in ethyl acetate. The product (Ex. No. 53, Table 2) was isolated as an orange solid, 0.79 g, m.p. 155°-160°C (dec). ¹ H-NMR (CDCl₃) ∂1.40-1.66 (m, 4H); 2.33 (m, 2H); 2.40 (s, 3H); 2.46 (m, 4H); 2.53 (s, 3H); 3.79 (m, 4H); 4.10 (t, 2H, J=6 Hz); 5.40 (s, 1H); 6.48 (t, 1H, J=6 Hz); 6.96 (s, 1H); 7.23 (m, 1H); 7.73 (m, 1H); 8.31 (d, 2H, J=6 Hz); 8.43 (m, 1H); 8.54 (d, 1H, J=1 Hz). IR (KBr): 3189, 2944, 1706, 1650, 1587, 1548, 1500, 1360, 1225 cm-1. Mass Spectrum: 494 (M+1), 522 (M+29), 219 (C₁2 H₁9 N₄).

EXAMPLE 77

Part A; 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, (2-chloroethyl) ester: A mixture of nitroacetone (6.82 g), 1-methyl-2-pyrrolecarboxaldehyde (4.80 g), (2-chloroethyl)-3-aminocrotonate (7.20 g) and 10 g molecular sieves in 200 ml ethanol was stirred at room temperature for 4 days. After removal of the solvent by rotary evaporation, the residue was purified via column chromatography on silica gel, eluting with 30% petroleum ether in diethyl ether, to give a brown solid, 2.36 g. ¹ H-NMR (CDCl₃) ∂2.49 (s, 3H); 2.52 (s, 3H); 3.66 (t, 2H, J=6 Hz); 3.87 (s, 3H); 4.35 (t, 2H, J=6 Hz); 5.29 (s, 1H); 5.89 (m, 1H); 5.97 (m, 1H); 6.16 (br. s, 1H); 6.43 (m, 1H).

Part B; 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester: A mixture of 1,4-dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecar boxylic acid, (2-chloroethyl) ester 1.36 g, 1.54 g of 1-(2-methoxyphenyl)piperazine, 133 mg of sodium iodide, and 0.7 g of sodium bicarbonate in 100 ml of DME was heated at reflux for 4 days. The solvent was removed by rotary evaporation, and the residue was partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (2×100 ml), the organic layers combined, washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, eluting with ethyl acetate. The product (Ex. No. 77, Table 2) was isolated as an orange solid, 0.71 g. ¹ H-NMR (CDCl₃) ∂2.38 (s, 3H); 2.51 (s, 3 H); 2.65 (m, 6H); 3.05 (s, 4H); 3.86 (s, 6H); 4.25 (t, 2H, J=6 Hz); 5.30 (s, 1H); 5.87 (t, 1H, J=2 Hz); 5.88 (s, 1H); 5.96 (t, 1H, J=3 Hz); 6.43 (t, 1H, J=3 Hz); 6.92 (m, 4H). IR (KBr): 3318, 3096, 2941, 2819, 1687, 1500, 1312, 1102, 1014, 750 cm-1. Mass Spectrum: 496 (M+1), 524 (M+29).

Other compounds which can be prepared by such procedures and procedures described in the synthesis disclosure are illustrated by the structures represented in Tables 1 and 2. These Tables are intended to illustrate the invention, but not limit its breadth.

TABLE 1
##STR27##
(I)
Ex. No. Cy R2 R3 R5 R6 mp °C.             1
##STR28##
CH3 NO2 CO2 CH3 CH3 94-105a
2
##STR29##
CH3 NO2 CO2 CH3 CH3 105-8b
3
##STR30##
CH3 NO2 CO2 CH3 CH3 123c
4
##STR31##
CH3 NO2 CO2 CH3 CH3 206d
5
##STR32##
CH3 NO2 CO2 CH3 CH3 97-111e
6
##STR33##
CH3 NO2 CO2 CH3 CH3 182-6f
7
##STR34##
CH3 NO2 CO2 CH3 CH3 164-6g
8
##STR35##
CH3 NO2 CO2 CH3 CH3 97-105h
9
##STR36##
CH3 NO2 CO2 CH3 CH3 80-84i
10
##STR37##
CH3 NO2 CO2 CH3 CH3 66-69j
11
##STR38##
CH3 NO2 CO2 CH3 CH3 glassysolidk   12
##STR39##
CH3 NO2 CO2 CH3 CH3
13
##STR40##
CH3 NO2 CO2 C2 H5 CH3
14
##STR41##
##STR42##
CO2 CH3 CH3
15
##STR43##
C2 H5 NO2 CO2 CH3 C2 H5   16
##STR44##
CH3 CN CO2 CH3 CH2 OH
17
##STR45##
CH3 H CO2 C3 H7 CH3
18
##STR46##
CH3 CONH2 CO2 CH3 CH3
19
##STR47##
CH3 NO2 CO2 C2 H5 CH3
20
##STR48##
C3 H7 H CO2 CH3 CH3
21
##STR49##
CH3 NO2 CO2 CH3 CH3
22
##STR50##
CN CONH2 CO2 CH3 CH3
23
##STR51##
CH2 OH NO2 CHO CH3
24
##STR52##
CH3 NO2 COCH3 CH3
25
##STR53##
CH3 CN CO2 C2 H5 CH3
26
##STR54##
CH3 CONH2 COCH3 CH3
27
##STR55##
C3 H7 NO2 CO2 CH2 CHOHC6 H5 CH3
28
##STR56##
CH3 NO2 CO2 C3 H7 CH3
29
##STR57##
##STR58##
CO2 CH3 CH3
30
##STR59##
CN CN CO2 CH3 CH3
31
##STR60##
CH3 CONH2 CO2 C2 H5 CH3
32
##STR61##
CH2 OH H CO2 CH3 C2 H5
33
##STR62##
CH3 CN CO2 CH3 CH3
34
##STR63##
NH2 NO2 CO2 CH3 CH3
35
##STR64##
C2 H5 NO2 CO2 CH3 C2 H5   36
##STR65##
CH3 NO2 COCH3 CH3
37
##STR66##
CH3 H CO2 CH3 CH3
38
##STR67##
CH2 OH NO2 CHO CH3
39
##STR68##
CH3 NO2 CONHC6 H5 CH3
40
##STR69##
CH3 CONH2 CO2 CH3 CH3
41
##STR70##
##STR71##
CO2 CH3 C2 H5
42
##STR72##
CH3 NO2 CO2 CH3 CH3
43
##STR73##
CH3 NO2 CHO CH3
44
##STR74##
CH3 NO2 CO2 CH2 CHOHC6 H5 CH3   45
##STR75##
CH3 NO2 CO2 C2 H5 CH3
46
##STR76##
CH3 CN CO2 CH3 C2 H5
47
##STR77##
##STR78##
CO2 C3 H7 CH3
48
##STR79##
CH3 NO2 CO2 CH3 CH3
49
##STR80##
C2 H5 CONH2 CO2 C2 H5 CH3        50
##STR81##
##STR82##
CO2
CH3 CH3
Footnotes for TABLE 1 a see text for spectral data. b1 H-NMR
(200 MHz, CDCl3) 8 1.44 (m, 2H); 1.61 (m, 8H); 2.37 (s, 3H); 2.45
(m, 2H); 2.51 (s, 3H); 2.73 (m, 2H); 3.70 (s, 3H); 3.88 (m, 4H); 5.32
(s, 1H); 6.12 (s, 2H); 6.52 (m, 1H); 7.00 (m, 1H); 7.17 (s, 1H); 7.53
(s, 1H). IR (KBr): 2943, 1707, 1616, 1490, 1436, 1225 cm-1. Mass
Spectrum: 527 (M + 1), 555 (M + 29). m.p.:105-108°C HRMS:
Calcd: 526.2427; Found: 526.2426; c1 H-NMR (200 MHz, CDCl3) a
1.68-2.05 (m, 4H); 2.24 (s, 3H); 2.46 (t, 2H, J-7Hz); 2.54 (s, 3H); 2.65
(m, 4H); 3.08 (m, 4H); 3.35 (m, 1H); 3.61 (s, 3H); 3.85 (s, 3H); 6.57
(s, 1H); 6.67 (s, 1H); 6.83-6.99 (m, 4H); d1 H-NMR (200 MHz,
d6 -DMSO) ∂ 1.95 (s, 4H); 2.35 (s, 3H); 2.57 (s, 3H);
2.89 (m, 2H); 3.14-3.22 (m, 6H); 3.49-3.62 (m, 7H); 3.81 (3, 3H); 5.76
(s, 1H); 6.92-7.06 (m, 4H); 7.31-7.36 (m, 1H); 7.43-7.52 (m, 2H);
7.87-7.90 (m, 1H); 10.24 (s, 1H). e1 H-NMR (200 MHz, CDCl3)
∂ 1.56 (m, 4H); 1.80 (t, 2H, J=7Hz); 2.31 (s, 3H); 2.48 (s,
3H); 2.54 (m, 6H); 3.59 (s, 3H); 3.84 (m, 4H); 3.95 (t, 2H, J=7Hz); 5.64
(s, 1H); 6.36 (s, 1H); 6.50 (m, 1H); 6.85 (m, 2H); 7.00 (d, 1H, J=2Hz);
7.14 (m, 1H); 7.29 (m, 1H); 7.48 (s, 1H). IR (KBr): 2945, 1706, 1619,
1491, 1307, 1225 cm-1. Mass Spectrum: 553 (M + 1), 249, 211. m.p.:
97-111°C HRMS: Calcd: 552.2584; Found: 552.2577 f1 H-NMR
(200 MHz, CDCl3) ∂ 1.50 (m, 2H); 1.91 (m, 2H); 2.05
(m, 4H); 2.31 (m, 2H); 2.39 (s, 3H); 2.62 (s, 3H); 2.80 (s, 3H); 3.04
(m, 2H); 3.58 (s, 3H); 3.62 (m, 2H); 3.83 (t, 2H, J=6Hz); 5.51 (s, 1H);
6.81 (m, 2H); 7.12 (m, 1H); 7.32 (m, 6H); 8.56 (s, 1H). IR (KBr): 2942,
1707, 1651, 1494, 1307 1224 cm-1. Mass Spectrum: 534 (M + 1), 562
(M + 29). m.p.: 182-6°C HRMS: Calcd: 533.2890; Found: 533.2879;
g1 H-NMR (200 MHz, CDCl3 ) ∂ 1.55 (m, 4H); 1.78
(m, 2H); 2.31 (s, 3H); 2.43 (m, 2H); 2.49 (s, 3H); 2.57 (m, 4H); 3.60
(s, 3H); 3.65 (m, 4H); 3.96 (t, 2H, J-6Hz); 5.64 (s, 1H); 6.55 (s, 1H);
6.77 (m, 1H); 6.82 (m, 1H); 6.91 (d, 1H, J=lOHz); 7.11 (m, IH); 7.22 (d,
1H, J=1OHz); 7.29 (m, 1H). IR (KBr): 2944, 1708, 1653, 1586, 1493, 1442,
1309, 1224 cm-1. Mass Spectrum: 571 (M + 1), 599 (m + 29). m.p.:
164-166°C h1 H-NMR (200 MHz, CDCl3) ∂
1.38 (d, 6H, J=6Hz); 1.51-1.83 (m, 6H); 2.32 (s, 3H); 2.43 (m, 2H); 2.49
(s, 3H); 2.60 (t, 4H, J=5Hz); 3.54 (t, 4H, J=5Hz); 3.60 (s, 3H); 3.92
(t, 2H,. J=6Hz); 5.42 (m, 1H); 5.62 (s, 1H); 6.29 (m, 1H); 6.79 (d, 1H,
J=9Hz); 6.81 (m, 2H); 7.02 (d, 1H, J=9Hz); 7.13 (m, IH); 7.27 (m, 1H).
IR (KBr): 3312, 2943, 1707, 1651, 1444, 1306, 1224 cm-1. Mass
Spectrum: 595 (M + 1), 623 (M +
29), 548, 563, 593.  m.p.: 97-105°C HRMS: Calcd: 594.3166;
Found: 594.3153; i1 H-NMR (200 MHz, CDCl3) ∂
1.46-1.66 (m, 4H); 1.66-1.86 (m, 2H); 2.31 (s, 3H); 2.36-2.59 (m, 6H);
2.46 (s, 3H); 3.50-3.86 (m, 4H); 3.60 (s, 3H); 3.96 (t, 2H, J=7Hz); 4.33
(dd, 1H, J=8, 12Hz); 4.50 (dd, 1H, J=2, 12Hz); 4.85 (dd, 1H, J=2, 8Hz);
5.66 (s, 1H); 6.22 (s, 1H); 6.73-6.96 (m, 6H); 7.07-7.26 (m, 2H). IR
(KBr): 3629, 3309, 2943, 2867, 1706, 1648, 1494, 1307, 1269, 1225, 1101,
1016, 751 cm-1. Mass Spectrum: 621 (M + 1), 649 (M + 29). m.p.:
80-84°C j1 H-NMR (200 MHz, CDCl3) ∂
1.52-1.66 (m, 4H); 1.78-1.85 (m, 2H); 2.32 (s, 3H); 2.42 (m, 2H); 2.48
(s, 3H); 2.58 (t, 4H, J=5Hz); 3.60 (s, 3H); 3.61 (m, 4H); 3.96 (t, 2H,
J=7Hz); 5.64 (s, 1H); 6.16 (s, 1H); 6.79 (m, 1H); 6.83 (m, IH); 7.12 (m,
IH); 7.26 (m, 1H); 7.85 (d, 1H, J=3Hz); 8.07 (m, 1H); 8.14 (d, IH,
J=lHz). IR (KBr): 3310, 3078, 2944, 1707, 1492, 1380, 1313, 1222, 1016
cm-1. Mass Spectrum: 537 (M + 1), 565 (M + 29). m.p.: 66-69°
C. HRMS: Calcd: 536.2747; Found: 536.2735. k1 H-NMR (200 MHz,
CDCl3) ∂ 1.03 (t, 3H, J=6Hz) 1.50-1.66 (m, 4H);
1.73-1.86 (m, 4H); 2.30 (s, 3H); 2.43 (m, 2H); 2.46 (s, 3H); 2.53 (m,
4H); 3.61 (m, 4H), 3.63 (s, 3H); 3.96 (t, 2H, J=7Hz); 4.24 (t, 2H,
J=6Hz); 5.66 (s, 1H); 5.82 (s, IH); 6.40 (s, 1H); 6.79-6.89 (m, 2H);
7.07-7.20 (m, 1H); 7.28 (m, 1H); 8.60 (s, 1H). IR (KBr): 3316, 3094,
2936, 1708, 1593, 1540, 1493, 1380, 1306, 1220, 1013, 750 cm-1.
Mass Spectrum: 595 (M + 1), 623 (M + 29). HRMS: Calcd: 593.3087; Found:
593.3031.

TABLE 2
__________________________________________________________________________
##STR83##                                                   (I)
Ex.
No.
Cy         R2
R3
R5                     R6
mp
__________________________________________________________________________
°C.
51
##STR84## CH3
NO2
##STR85##                  CH3
glassy solid
a
52
##STR86## CH3
NO2
##STR87##                  CH3
155-160b
53
##STR88## CH3
NO2
##STR89##                  CH3
155-160c
(dec)
54
##STR90## CH3
NO2
##STR91##                  CH3
77-80d
55
##STR92## CH3
NO2
##STR93##                  CH3
51-61e
56
##STR94## CH3
NO2
##STR95##                  CH3
50-54f
57
##STR96## CH3
NO2
##STR97##                  CH3
52-56g
58
##STR98## CH3
NO2
##STR99##                  CH3
51-55h
59
##STR100##
CH3
NO2
##STR101##                 CH3
59-63i
60
##STR102##
CH3
NO2
##STR103##                 CH3
65-72j
61
##STR104##
CH3
NO2
##STR105##                 CH3
160-178k
62
##STR106##
CH3
NO2
##STR107##                 CH3
197-200l
(dec)
63
##STR108##
CH3
NO2
##STR109##                 CH3
57-62m
64
##STR110##
CH3
NO2
##STR111##                 CH3
glassy solid
n
65
##STR112##
CH3
NO2
##STR113##                 CH3
glassy solid
o
66
##STR114##
CH3
NO2
##STR115##                 CH3
58-63p
67
##STR116##
CH3
NO2
##STR117##                 CH3
glassy solid
q
68
##STR118##
CH3
NO2
##STR119##                 CH3
glassy solid
r
69
##STR120##
CH3
NO2
##STR121##                 CH3
glassy solid
s
70
##STR122##
CH3
NO2
##STR123##                 CH3
glassy solid
t
71
##STR124##
CH3
NO2
##STR125##                 CH3
glassy solid
u
72
##STR126##
CH3
NO2
##STR127##                 CH3
glassy solid
v
73
##STR128##
CH3
NO2
##STR129##                 CH3
62-66w
74
##STR130##
CH3
CN
##STR131##                 CH3
62-65x
75
##STR132##
CH3
NO2
##STR133##                 CH3
glassy solid
y
76
##STR134##
CH3
NO2
##STR135##                 CH
glassy solid
z
77
##STR136##
CH3
NO2
##STR137##                 CH3
glassy solid
aa
78
##STR138##
CH3
NO2
##STR139##                 CH3
glassy solid
bb
79
##STR140##
CH3
NO2
##STR141##                 CH3
80
##STR142##
CH3
CONH2
##STR143##                 CH3
81
##STR144##
##STR145##
##STR146##                 CH3
82
##STR147##
CH3
NO2
##STR148##                 CN
83
##STR149##
CH2 OH
NO2
##STR150##                 CH3
84
##STR151##
CH3
H
##STR152##                 CH3
85
##STR153##
CH3
CN
##STR154##                 CH3
86
##STR155##
CH3
H
##STR156##                 CN
87
##STR157##
##STR158##
##STR159##                 CH3
88
##STR160##
C2 H5
NO2
##STR161##                 CH3
89
##STR162##
C3 H7
NO2
##STR163##                 C3 H7
90
##STR164##
CH2 OH
CN
##STR165##                 CH3
91
##STR166##
CH3
NO2
##STR167##                 CH2 OH
92
##STR168##
##STR169##
##STR170##                 CN
93
##STR171##
CH2 OH
CN
##STR172##                 CH3
94
##STR173##
CH3
NO2
##STR174##                 CH3
95
##STR175##
C2 H5
NO2
##STR176##                 C2 H5
96
##STR177##
CN   CN
##STR178##                 CH3
97
##STR179##
CH3
NO2
##STR180##                 CH3
98
##STR181##
##STR182##
--
##STR183##                 C2 H5
99
##STR184##
CH2 OH
NO2
##STR185##                 CH2 OH
100
##STR186##
CH3
CONH2
##STR187##                 CH3
__________________________________________________________________________
Footnotes for Table 2
a1 H-NMR(200 MHz, CDCl3)∂ 1.55(m, 4H); 2.35(s,
3H); 2.38(m, 2H); 2.54(s, 3H); 2.63(m, 4H); 3.10(m, 4H); 3.87(s, 3H);
4.08(t,
2H, J=6Hz); 5.81(s, 1H); 6.95(m, 3H); 7.35-7.50(m, 4H); 7.69(d, 1H,
J=9Hz). Mass Spectrum: 563(M + 1), 591(M + 29).
b1 H-NMR(200 MHz, CDCl3)∂ 1.50(m, 2H); 1.61(m,
2H); 2.38(s, 3H); 2.40(m, 1H); 2.53(s, 3H); 2.63(m, 4H); 3.10(m,4H);
3.87(s, 3H);
4.08(t, 2H, J=6Hz); 5.38(s, 1H); 6.85-7.08(m, 4H); 7.25(m, 1H); 7.39(s,
1H); 7.74(d, 1H, J=8Hz); 8.42(d, 1H, J=3Hz); 8.50(d, 1H,
J=2Hz). IR(KBr): 2940, 2816, 1705, 1646, 1501, 1466, 1310, 1272, 1225
cm-1. Mass Spectrum: 522(M + 1), 550(M + 29),
247(C15 H23 N2 O). m.p.: 155-160°C
c see text for spectral data
d1 H-NMR(200 MHz, CDCl3)∂ 1.53(m, 2H); 1.61(m,
2H); 2.35(m, 2H); 2.37(s, 3H); 2.46(t, 4H, J=5Hz); 2.55(s, 3H); 3.82(t,
4H, J=5Hz); 4.07(t, 2H, J=7Hz); 5.81(s, 1H); 6.50(t, 1H, J=5Hz); 6.53(s,
1H); 7.34(dd, 1H, J=6, 9Hz); 7.46(d, 1H, J=6Hz);
7.68(d, 1H, J=9Hz); 8.31(d, 2H, J=5Hz). IR(KBr): 3500, 3308, 3212, 3084,
2946, 1705, 1587, 1548, 1498, 1449, 1359, 1311, 1262, 1221,
1105, 1014, 983, 797, 752 cm-1. Mass Spectrum: 535(M + 1), 563(M +
29). m.p.: 77-80°C
e1 H-NMR(200 MHz, CDCl3)∂ 2.39(s, 3H); 2.51(s,
3H); 2.71(m, 6H); 3.05(m, 4H); 3.87(s, 3H); 4.25-4.39(m, 2H); 5.43(s,
1H); 6.32(s,
1H); 6.84-7.03(m, 5H); 7.29(m, 2H). IR (KBr): 3510, 3315, 3230, 3090,
2940, 2830, 1708, 1650, 1500, 1450, 1385, 1320, 1280, 1240, 1150,
1110, 1010, 750 cm-1. Mass Spectrum: (483(M + 1), 511(M + 29). m.p.:
57-61°C HRMS: Calcd: 482.2165; Found:482.2154
f1 H-NMR(200 MHz, CDCl3)∂ 2.39(s, 3H); 2.52(s,
3H); 2.53(m, 4H); 2.67(m, 2H); 3.80(t, 4H, J=5Hz); 4.20(m, 1H);
4.36(m, 1H); 5.42(s, 1H); 6.08(s, 1H); 6.32(s, 1H); 6.49(t, 1H, J=5Hz);
7.28(m, 2H); 8.31(d, 2H, J=5Hz). IR (KBr): 3500, 3302, 3100,
2950, 2820, 1700, 1685, 1653, 1586, 1548, 1497, 1450, 1360, 1313, 1260,
1229, 1151, 1106, 1017, 984, 797 cm-1. Mass Spectrum:
455(M + 1), 483(M + 29). m.p.: 50-54°C HRMS: Calcd: 454.1964;
Found: 454.1969
g1 H-NMR(200 MHz, CDCl3)∂ 1.51-1.70(m, 4H);
2.37(s, 3H); 2.39(m, 2H); 2.51(s, 3H); 2.61(m, 4H); 3.09(m, 4H); 3.85(s,
3H);
3.87(s, 3H); 4.14(m, 2H); 5.29(s, 1H); 5.86(m, 1H); 5.96(m, 2H); 6.42(t,
1H, J=2Hz); 6.84-7.00(m, 4H). IR (KBr): 3500, 3310, 3093, 2943
2818, 1700, 1684, 1652, 1500, 1456, 1380, 1313, 1221, 1102, 1013, 814,
750 cm-1. Mass Spectrum: 524(M + 1), 552(M + 29).
m.p.: 52-56°C
h1 H-NMR(200 MHz, CDCl3)∂ 1.48-1.66(m, 4H);
2.35(m, 2H); 2.37(s, 3H); 2.46(m, 4H); 2.52(s, 3H); 3.80(m, 4H); 3.84(s,
3H);
4.12(m, 2H); 5.28(s, 1H); 5.86(m, 1H); 5.97(m, 2H); 6.42(m, 1H); 6.47(t,
1H, J=5Hz); 8.32(d, 2H, J=5Hz). IR (KBr): 3500, 3310, 3210,
3092, 2943, 2851, 1700, 1684, 1653, 1586, 1549, 1497, 1448, 1388, 1360,
1311, 1290, 1262, 1220, 1101, 1013, 983, 797, 701 cm-1.
Mass Spectrum: 496(M + 1), 524(M + 29). m.p.:51-55°C
i1 H-NMR(200 MHz, CDCl3)∂ 2.40(s, 3H); 2.53(s,
3H); 2.66-2.79(m, 6H); 3.00-3.17(m, 4H); 3.86(s, 3H); 4.17-4.43(m,
2H); 5.63(s, 1H); 6.07(s, 1H); 6.18(m, 1H); 6.26(m, 1H); 6.82-7.07(m,
4H); 7.23(m, 1H). IR (KBr): 3500, 3310, 3230, 3075, 2942, 2822,
1701, 1684, 1652, 1500, 1456, 1381, 1316, 1272, 1225, 1150, 1103, 1011,
800, 747 cm-1. Mass Spectrum: 483(M + 1),
511(M + 29). m.p. 59-63°C HRMS: Calcd: 482.2165; found:
482.2164
j1 H-NMR(200 MHz, CDCl3)∂ 2.40(s, 3H); 2.53(m,
4H); 2.54(s, 3H); 2.68(t, 2H, J=6Hz); 3.80(m, 4H); 4.23-4.35(m, 2H);
5.62(s, 1H); 6.09(s, 1H); 6.15(d, 1H, J=3Hz); 6.25(m, 1H); 6.49(t, 1H,
J=5Hz); 7.23(d, 1H, J=2Hz); 8.30(d, 2H, J=5Hz). IR (KBr):
3546, 3310, 3094, 2941, 2822, 1706, 1648, 1586, 1548, 1490, 1449, 1360,
1314, 1261, 1224, 1152, 1102, 1010, 982, 797, 739 cm-1.
Mass Spectrum: 455(M + 1), 483(M + 29). m.p.: 65-72°C HRMS:
Calcd: 454.1964; Found: 454.1969
k1 H-NMR(200 MHz, CDCl3)∂ 2.40(s, 3H); 2.54(s,
3H); 2.64(m, 6H); 3.05(m, 4H); 3.87(s, 3H); 4.22(t, 2H, J=6Hz);
5.42(s, 1H); 6.84-7.00(m, 4H); 7.08(m, 1H); 7.21(m, 1H); 7.77(d, 1H,
J=8Hz); 8.42(m, 1H); 8.52(d, 1H, J=2Hz). IR (KBr):
3500, 3296, 3174, 3057, 2933, 2829, 1705, 1642, 1592, 1500, 1450, 1377,
1309, 1270, 1222, 1145, 1101, 1021, 753 cm-1. Mass
Spectrum: 494(M + 1), 522(M + 29). m.p.: 160-178°C
l1 H-NMR(200 MHz, CDCl3)∂ 2.39(s, 3H); 2.48(m,
4H(); 2.53(s, 3H); 2.60(t, 2H, J=6Hz); 3.77(m, 4H); 4.21(m, 2H);
5.41(s, 1H); 6.49(t, 1H, J=5Hz); 7.22(m, 2H); 7. 76(d, 1H, J=8Hz);
8.30(d, 2H, J=5Hz); 8.41(m, 1H); 8.52(d, 1H, J=2Hz). IR
(KBr): 3500, 3190, 3062, 2936, 1682, 1587, 1546, 1506, 1307, 1234, 1105,
1016, 984, 780 cm-1. Mass Spectrum:
466(M + 1), 494(M + 29). m.p.: 197-200°  C. (dec).
m1 H-NMR(200 MHz, CDCl3)∂ 1.36-1.69(m, 4H);
2.38(m, 2H); 2.40(s, 3H); 2.53(s, 3H); 2.62(m, 4H); 3.08(m, 4H);
3.87(s, 3H); 4.14(m, 2H); 5.77(s, 1H); 6.08(s, 1H); 6.82-7.03(m, 4H);
6.86(m, 2H); 7.09(m, 1H). IR (KBr): 3500, 3304, 3065,
2942, 2817, 1704, 1642, 1501, 1314, 1272, 1228, 1103, 749 cm-1. Mass
Spectrum: 527(M + 1), 555(M + 29).
m.p.: 57-62°C
n1 H-NMR(200 MHz, CDCl3)∂ 1.51(m, 2H); 1.66(m,
2H); 2.36(m, 2H); 2.40(s, 3H); 2.46(m, 4H); 2.53(s, 3H);
3.82(m, 4H); 4.16(m, 2H); 5.76(s, 1H); 6.43(s, 1H); 6.46(m, 1H); 6.87(m,
2H); 7.10(m, 1H); 8.30(m, 2H). IR (KBr): 3500,
3306, 3068, 2939, 1706, 1586, 1548, 1492, 1359, 1312, 1226, 1012, 982,
795 cm-1. Mass Spectrum: 499(M + 1),
527(M + 29).
o1 H-NMR(200 MHz, CDCl3)∂ 2.40(s, 3H); 2.52(s,
3H); 2.69(m, 6H); 3.05(m, 4H); 3.87(s, 3H); 4.22-4.33(m, 2H);
5.60(s, 1H); 6.06(s, 1H); 6.84-7.00(m, 3H); 7.03(m, 2H); 7.12(m, 2H). IR
(KBr): 3500, 3309, 2941, 2822, 1703, 1500, 1314,
1226, 1104, 1015, 749 cm-1. Mass Spectrum: 499(M + 1), 527(M +
29)..
p1 H-NMR(200 MHz, CDCl3)∂ 2.40(s, 3H); 2.46(m,
4H); 2.52(s, 3H); 2.64(t, 2H, J=6Hz); 3.78(m, 4H); 4.18(m, 1H);
4.34(m, 1H); 5.59(s, 1H); 6.01(s, 1H); 6.48(t, 1H, J=5Hz); 7.03(m, 1H);
7.09(s, 1H); 7.17(m, 1H); 8.29(d, 2H, J=5Hz). IR
(KBr): 3500, 3312, 3094, 2943, 1703, 1586, 1548, 1492, 1360, 1311, 1262,
1225, 1104, 1015, 983 cm-1. Mass Spectrum:
471(M + 1), 499(M + 29). m.p.: 58-63°C HRMS: Calcd: 470.1736;
Found: 470.1731
q1 H-NMR(200 MHz, CDCl3)∂ 1.49-1.61(m, 2H);
1.62-1.73(m, 2H); 2.37(s, 3H); 2.44(m, 2H); 2.50(s, 3H); 2.62(m,
4H); 3.10(m, 4H); 3.87(m, 3H); 4.16(m, 2H); 5.41(s, 1H); 6.22(s, 1H);
6.28(s, 1H); 6.84-7.04(m, 4H); 7.27(m, 2H); IR (KBr):
3310, 2944, 2818, 1703, 1652, 1500, 1315, 1230, 1106, 1017, 750
cm-1. Mass Spectrum: 511(M + 1), 539(M + 29).
r1 H-NMR(200 MHz, CDCl3)∂ 1.50-1.62(m, 2H);
1.68(m, 2H); 2.33-2.44(m, 2H); 2.38(s, 3H); 2.48(m, 4H);
2.50(s, 3H); 3.82(t, 4H, J=5Hz); 4.07-4.19(m, 2H); 5.41(s, 1H); 6.28(d,
1H, J=1Hz); 6.36(s, 1H); 6.48(t, 1H, J=5Hz);
7.24(s, 1H); 8.29(d, 2H, J=5Hz). IR (KBr): 3312, 2950, 1702, 1586, 1548,
1492, 1359, 1313, 1229, 1106, 1015, 753 cm-1.
Mass Spectrum: 482(M+).
s1 H-NMR(200 MHz, CDCl3l )∂ 1.52-1.73(m, 4H);
2.39(s, 3H); 2.42(m, 2H); 2.54(s, 3H); 2.64(m, 4H); 3.10(m, 4H);
3.87(s, 3H); 4.15(m, 2H); 5.61(s, 1H); 6.10(d, 1H, J=3Hz); 6.17(s, 1H);
6.24(m, 1H); 6.84 -7.01(m, 4H); 7.21(d, 1H,
J=2Hz). IR (film): 3312, 2945, 2819, 1703, 1500, 1316, 1230, 1011, 750
cm-1. Mass Spectrum: (M + 1),
(M + 29). HRMS: Calcd: 510.2478; Found: 510, 2466
t1 H-NMR(200 MHz, CDCl3)∂ 1.54(m, 2H);
1.60-1.71(m, 2H); 2.35-2.42(m, 2H); 2.39(s, 3H);
2.48(t, 4h, J=5Hz); 2.54(s, 3H); 3.82(t, 4H, J=5Hz); 4.15(m, 2H); 5.61(s,
1H); 6.10(d, 1H, J=3Hz);
6.16(s, 1H); 6.24(t, 1H, J=3Hz); 6.47(t, 1H, J=5Hz); 7.22(s, 1H); 8.30(d,
2H, J=5Hz). IR (film): 3314,
2947, 1704, 1586, 1548, 1494, 1359, 1315, 1224, 1011, 984, 742 cm-1.
Mass Spectrum: 483(M + 1),
(511(M +29).
u1 H-NMR(200 MHz, CDCl3)∂ 1.54(m, 2H); 1.64(m,
2H); 2.33(s, 3H); 2.40(t, 2H, J=7Hz);
2.47(s, 3H); 2.62(s, 4H); 3.09(s, 4H); 3.85(s, 3H); 4.12(d, 2H>J=5Hz);
5.56(s, 1H); 6.84-
7.01(m, 4H); 7.03(m, 2H); 7.15(m, 1H); 7.36(s, 1H). IR (film): 3314,
2943, 2818, 1702, 1500, 1312, 1226,
1014, 751 cm-1. Mass Spectrum: 527(M + 1), 555(M + 29).
v1 H-NMR(200 MHz, CDCl3)∂ 1.50(m, 2H); 1.64(m,
2H); 2.35(t, 2H, J=7Hz); 2.40(s, 3H); 2.46(t,
4H, J=5Hz); 2.52(s, 3H); 3.82(t, 4H, J=5Hz); 4.12(m, 2H); 5.57(s, 1H);
5.99(s, 1H); 6.48(t, 1H, J=5Hz);
7.01(m, 2H); 7.17(m, 1H); 8.30(d, 2H, J=5Hz). IR (KBr): 3314, 3097, 2946,
1702, 1586, 1547, 1492, 1359,
1312, 1226, 1014, 983, 796 cm-1. Mass Spectrum: 499(M + 1), 527(M +
29). HRMS: Calcd:
498.2049; Found: 498.2060.
w1 H-NMR(200 MHz, CDCl3)∂ 2.43(s, 3H); 2.48(m,
4H); 2.53(s, 3H); 2.66(t, 2H, J=5Hz); 3.77(m, 4H);
4.23(m, 1H); 4.33(m, 1H); 5.78(s, 1H); 6.00(s, 1H); 6.48(t, 1H, J=5Hz);
6.88(m, 1H); 6.92(d, 1H, J=2Hz); 7.11(m,
1H); 8.29(d, 2H, J=5Hz). IR (KBr): 3308, 3089, 2941, 1705, 1586, 1548,
1491, 1360, 1311, 1227, 1014, 983
cm-1. Mass Spectrum: 471(M + 1), 499(M + 29). m.p.: 63-66°C
HRMS: Calcd: 470.1736;
Found: 470.1735.
x1 H-NMR(200 MHz, CDCl3)∂ 2.43(s, 3H); 2.53(s,
3H); 2.66(m, 4H); 2.70(m, 2H); 3.05(m, 4H); 3.87(m, 3H);
4.26-4.34(m, 2H); 5.79(s, 1H); 6.03(s, 1H); 6.84-7.03(m, 6H); 7.11(m,
1H). IR (KBr): 3311, 3068, 2940, 2821, 1705,
1500, 1381, 1314, 1230, 1015, 750 cm-1. Mass Spectrum: 499(M + 1),
527(M + 29). m.p.:62-65°C
HRMS: Calcd: 498.1936; Found: 498.1942
y1 H-NMR(200 MHz, CDCl3)∂ 2.38(s, 3H); 2.56(s,
3H); 2.57-2.67(m, 6H); 3.03(m, 4H); 3.87(s, 3H); 4.19(m,
2H); 5.82(s, 1H); 6.30(s, 1H); 6.85-7.04(m, 4H); 7.34(m, 1H); 7.52(d, 1H,
J=7Hz); 7.68(d, 1H, J=9Hz). IR (KBr):
3323, 3094, 2941, 2820, 1707, 1500, 1312, 1223, 1015, 750 cm-1. Mass
Spectrum: 535(M + 1), 563(M + 29).
HRMS: Calcd: 534.2227; Found: 534.2219.
z1 H-NMR(200 MHz, CDCl3)∂  2.38(s, 3H); 2.49(t,
4H, J=5Hz); 2.56(s, 3H); 2.61(m, 2H); 3.77(t, 4H, J=5Hz);
2.56(s, 3H); 2.61(m, 2H); 3.77(t, 4H, J=5Hz); 4.20(m, 2H); 5.82(s, 1H);
6.25(s, 1H); 6.49(t, 1H, J=5Hz); 7.34(dd, 1H,
J=7, 9Hz); 7.50(d, 1H, J=7Hz); 7.69(d, 1H, J=9Hz); 8.31(d, 2H, J=5Hz). IR
(KBr): 3330, 3100, 2950, 2830, 1710,
1585, 1545, 1500, 1360, 1305, 1230, 1100, 1012, 980, 748 cm-1. Mass
Spectrum: 507(M + 1), 535(M + 29).
aa see text for spectral data.
bb1 H-NMR(200 MHz, CDCl3)∂ 2.38(s, 3H); 2.49(t,
4H, J=5Hz); 2.52(s, 3H); 2.62(t, 2H, J=6Hz); 3.78(t, 4H,
J=5Hz); 3.86(s, 3H); 4.26(m, 2H); 5.30(s, 1H); 5.87(dd, 1H, J=2, 3Hz);
5.92(s, 1H); 5.97(t, 1H, J=3Hz); 6.42(t,
1H, J=2Hz); 6.49(t, 1H, J=5Hz); 8.30(d, 2H, J=5Hz). IR (KBr): 3319, 3096,
2941, 2850, 1704, 1586, 1548, 1492, 1360,
1310, 1221, 1102, 1014, 983 cm-1. Mass Spectrum: 468(M + 1), 496(M +
29). HRMS: Calcd: 467.2281; Found: 467.2267.

Utility

The compounds of this invention have been found to possess both Ca²+ channel activity, preferably Ca² + agonist activity, and alpha₁ -antagonist activity. These pharmacological properties of the compounds of this invention were evaluated in the following pharmacological experiments.

Determination of Affinity for alpha₁ -Adrenoceptors

The [³ H]-prazosin binding assay was carried out according to the method described by Timmermans, P. B. M. W. M., Schoop, A. M. C., and Van Zwieten, P. A., Biochem. Pharmacol., 31, 899-905, (1982). The reaction mixture contained partially purified rat brain membranes (source of alpha₁ -adrenoceptors), 0.2 nM [³ H]-prazosin with or without potential displacer in Tris buffer. The mixture was incubated for 60 minutes at 25°C and subsequently terminated by rapid filtration through glass fiber-filter. Receptor-bound [3H]-prazosin trapped in the filter was quantitated by scintillation counting. The inhibitory concentration (IC₅0) of potential displacer which gives 50% displacement of the total specifically bound [³ H]-prazosin is presented as a measure of the affinity of such compound for the alpha₁ -adrenoceptor.

Determination of Affinity for Calcium Channels

[3H]-Nitrendipine binding assay was carried out according to the method described by G. T. Bolger, et al., Biochem. Biophys. Res. Comm., 104, 1604-1609, (1982). The reaction mixture contained rat cardiac microsomes (source of Ca²+ channels), 0.5 nM [³ H]-nitrendipine with or without potential displacer in Tris buffer. The mixture was incubated for 60 minutes at 25°C and subsequently terminated by rapid filtration through a glass fiber-filter. Membrane-bound [³ H]-nitrendipine trapped in the filter was quantitated by scintillation counting. The inhibitory concentration (IC₅0) of potential displacer which gives 50% displacement of the total specifically bound [³ H]-nitrendipine is presented as a measure of the affinity of such compound for the Ca²+ channel. The results from the above two in vitro assays are summarized in Table 3.

TABLE 3
______________________________________
Binding Affinity Data for Calcium and
Alpha1 -adrenoceptors
[3 H]-Nitrendipine
[3 H]-Prazosin
Example No. binding IC50 [M]
binding IC50 [M]
______________________________________
1          6.0 × 10-7
1.3 × 10-7
2          1.5 × 10-6
1.9 × 10-6
3          2.4 × 10-7
6.3 × 10-8
4          8.9 × 10-7
2.0 × 10-8
5          6.8 × 10-7
2.2 × 10-6
6          3.6 × 10-7
9.0 × 10-7
7          6.5 × 10-7
1.9 × 10-6
8          5.8 × 10-7
1.5 × 10-5
9          9.5 × 10-7
5.2 × 10-6
10          1.2 × 10-6
7.2 × 10- 6
11          3.6 × 10-7
5.3 × 10-6
51          1.1 × 10-7
1.2 × 10-7
52          3.9 × 10-6
5.2 × 10-8
53          4.4 × 10-6
4.0 × 10-7
54          2.9 × 10-7
8.2 × 10-7
55          5.1 × 10-6
1.0 × 10-7
56          4.3 × 10-6
5.2 × 10-6
57          1.3 × 10-6
3.3 × 10-8
58          1.8 × 10-6
7.5 × 10-7
59          1.5 × 10-6
1.0 × 10-7
60          2.0 × 10-6
5.9 × 10-6
61          1.3 × 10-6
2.5 × 10-8
62          3.7 × 10-6
>1.0 × 10-6
63          2.2 × 10-6
6.0 × 10-8
64          1.2 × 10-6
1.2 × 10-6
65          8.6 × 10-7
1.8 × 10-7
66          9.5 × 10-7
6.0 × 10-6
67          3.5 × 10-6
6.3 × 10-8
68          2.7 × 10-6
8.5 × 10-7
69          2.0 × 10-6
3.5 × 10-8
70          2.0 × 10-6
8.4 × 10-7
71          1.7 × 10-6
7.8 × 10-8
72          1.6 × 10-6
1.0 × 10-6
73          2.4 × 10-6
4.9 × 10-6
74          1.9 × 10-6
1.2 × 10-7
75          8.5 × 10-8
4.7 × 10-7
76          8.5 × 10-8
1.7 × 10-5
77          1.1 × 10-6
1.1 × 10-7
78          1.7 ×  10-6
3.3 × 10-6
______________________________________

Protocol for Positive Inotropic Effect in Guinea Pig

PAC Left Atria

Guinea pigs are killed by cervical dislocation. The left atria are removed and mounted at 1 gm resting tension in tissue baths containing oxygenated Krebs bicarbonate solution which is kept at 37°C The left atria are electrically paced at 2 Hz with square wave pulses of 1 msec duration. The voltage is set at 1.5×threshold level.

After a one hour equilibration period, control values for developed tension (DT, gm) are recorded. Test compounds are then added to the baths, in a cumulative manner to a maximum concentration of 10-4, to obtain a concentration-response curve. Treatment values of DT are obtained after the drug effect has reached a plateau and the exposure time for each concentration is 5-8 minutes. Percent change of the treatment value from the control value is calculated at each concentration of the test compound. The results are shown in Table 4 below.

TABLE 4
______________________________________
Intrinsic
Example No.     EC50 (M)a
Activityb
______________________________________
Control-Bay K8644
1.5 × 10-7
100
1              5.0 × 10-6
188
2              9.6 × 10-5
144
3              1.0 × 10-6
89
4              --           43
5              3.0 × 10-6
269
6              2.0 × 10-6
207
7              1.2 × 10-5
149
8              1.5 × 10-5
113
9              5.3 × 10-5
62
10              2.8 × 10-6
55
11              4.3 × 10-5
68
51              1.1 × 10-5
175
52              --           35
53              2.5 × 10-5
189
54              >1.0 × 10-4
21
55              1.0 × 10-6
169
56              4.3 × 10-7
171
57              2.3 × 10-6
110
58              8.4 × 10-7
195
59              2.7 × 10-6
98
60              1.6 × 10-6
140
61              1.5 × 10-6
164
62              >1.0 × 10-4
48
63              1.2 × 10-5
75
64              3.4 × 10-6
76
65              1.0 × 10-6
225
66              8.5 × 10-7
210
67              2.4 × 10-5
86
68              3.7 × 10-6
147
69              6.2 × 10-5
60
70              5.0 × 10-6
132
71              --           40
72              1.2 × 10-5
70
73              9.8 × 10-7
84
74              6.3 × 10-7
173
75              4.0 × 10-7
82
76              5.6 × 10-8
156
77              2.3 × 10-7
240
78              5.8 × 231-7
______________________________________
a EC50 (m) = concentration that increases DT by 50% above the
control DT.
b Intrinsic Activity is a ratio of the maximum effect of the test
compound to that of Bay K8644 and expressed in percent.

The foregoing test results suggest that compounds of this invention have utility in the treatment of congestive heart failure.

Dosage Forms

Compounds of this invention can be administered to treat said deficiencies by any means that produces contact of the active agent with the agent's site of action in the body of the mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. For use in the treatment of said diseases, a daily dosage of active ingredient can be about 50 to 1000 mg.

Dosage forms (compositions) suitable for administration contain about 1 milligram to about 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions or parenterally, in sterile liquid dosage forms. Alternatively it can be administered sublingually by tablets, gels, pastes, patches or lozenges.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets can be sugar coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Useful pharmaceutical dosage forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredients, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.

Claims

1. A compound of the formula: ##STR188## or a pharmaceutically acceptable salt thereof or an optically active isomer or n-oxide thereof wherein:

R² and R⁶ independently are alkyl of 1-4 carbon atoms, CN, CH₂ OH or CH₂ OCH₂ CH₂ NH₂ ;

R³ independently is NO₂, H, CN, or CONH₂ ;

R⁵ is CHO, COCH₃, CO₂ CH₂ CH(OH)C₆ H₅, CO₂ CH₂ CH(OCH₃)C₆ H₅, NO₂, CONHC₆ H₅ or an alkyl ester of 1-10 carbons atoms;

Cy is: ##STR189## R¹ and R⁹ independently are H, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen or NO₂ ;

X is SO, SO₂, NR⁴, O, S or N→O;

Y is CH₂, ##STR190## R⁴ is H or an alkyl group of 1-4 carbon atoms; R⁷ is ##STR191## A is a straight or branched alkyl, alkenyl, or alkynyl chain or --(CH₂)_n CHOHCH₂ --;

R¹0 is ##STR192## or 2-, 3- or 4-pyridinyl, 2- or 4-pyrimidinyl or 2-pyrazinyl; Ar is phenyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, or NO₂, provided that Ar is not 4-fluorophenyl;

n is independently 1-4;

p is 1 to 10.

2. A compound of claim 1 wherein R² is CH₃.

3. A compound of claim 1 wherein R³ is NO₂.

4. A compound of claim 1 wherein

Cy is ##STR193## and R⁵ is an alkyl ester of 1-4 carbon atoms.

5. A compound of claim 4 wherein R¹ is H.

6. A compound of claim 4 wherein X is O or SO₂.

7. A compound of claim 1 which is 4-(2-(5-(4-(6-chloro-3-pyridazinyl)-1-piperazinyl)pentyloxy)phenyl)-1,4-di hydro-2,6-dimethyl-5-nitro-3-pyridine carboxylic acid, methyl ester.

8. A compound of claim 1 which is 4-(2-(5-(4-(6-(1-methylethoxy)-3-pyridazinyl)-1-piperazinyl)pentyloxy)phen yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridine carboxylic acid, methyl ester.

9. A compound of claim 1 which is 4-(2-(5-(4-(2-pyrazinyl)-1-piperazinyl)pentyloxy)phenyl)-1,4-dihydro-2,6-d imethyl-5-nitro-3-pyridine carboxylic acid, methyl ester.

10. A compound of claim 1 which is 4-(2-(5-(4-(6-propoxy-4-pyrimidinyl)-1-piperazinyl)pentyloxy)phenyl)-1,4-d ihydro-2,6-dimethyl-5-nitro-3-pyridine carboxylic acid, methyl ester.